Drug-resistant tuberculosis treatment

Obtain signed patient informed consent – consent should be obtained after giving detailed explanations 
on the novel nature of the regimen and pretomanid, including the risks and benefits of the regimen. 
The GDG members thought that informed consent should not be overly burdensome for patients; 
consent forms should be adapted, contextualized, streamlined and provided in the local language(s) 
so that they are easy for patients to understand; and patients should be fully informed about the 
regimen, given that it also includes a new compound, pretomanid. As part of the informed consent 
process, patients should
be:
• 
offered sufficient information on potential adverse events including low blood cell counts (e.g. 
anaemia, thrombocytopenia and neutropenia), liver toxicities, and peripheral and optic
neuropathy;
• 
advised that reproductive toxicities have been observed in animal studies, and that the potential 
effects on human male fertility have not been adequately evaluated at this time; and
• 
informed that pretomanid is excreted in breast milk, and its safety in infants and children has not 
been adequately evaluated (94). 
A medication guide is available as part of the pretomanid product label; this guide may be used when 
informing patients about the BPaL regimen as part of a research study. 
Administer treatment under closely monitored conditions – the aim is to enable optimal drug 
effectiveness and safety, and to monitor for the acquisition of emerging drug resistance, should it 
arise. Given that the regimen is a shorter regimen (i.e. it includes a new compound – pretomanid) 
and that its implementation is in the context of research, it may be especially important to monitor 
clinical progress after completion of treatment, to ensure relapse-free cure. Other design features 
of the Nix-TB study have implications for its implementation under operational research conditions. 
In the Nix-TB study, all medications were administered with food throughout and study medications 
were supervised according to local site practices, as a form of patient support. Preventing treatment 
interruption increases the likelihood of treatment success. Measures to support patient adherence 
(e.g. by facilitating patient visits to health care facilities or home visits by health care staff or by using 
digital technologies for daily communication) may be important to retain patients on treatment, even 

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WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
51
though the regimen is comparatively short (29). WHO recommendations on the care and support of 
patients with MDR/RR-TB are provided in 
Section 8
. 
Active pharmacovigilance and proper management of adverse drug reactions, and prevention of 
complications from drug–drug interactions – the NTP should actively monitor drug safety to ensure 
proper patient care, to report any adverse drug reactions to the responsible drug-safety authority in 
the country, and to inform national and global policy. 
The implementation of the BPaL regimen in the context of operational research implies
that:
• 
a study protocol has been developed by appropriately skilled and experienced researchers, 
and that this research protocol has been submitted to a national ethics board or other ethical 
approval
committee;
• 
prespecified inclusion and exclusion criteria are in place (noting the criteria used for the Nix-TB 
study);
54
• 
an appropriate schedule of safety monitoring and reporting is in place, including aDSM – usually 
overseen by a data safety monitoring board or similar independent research governance
committee;
• 
a predefined schedule of clinical and microbiological monitoring is in place, preferably including 
post-treatment completion follow-up; 
• 
individual patient informed consent is
obtained;
• 
patient support is provided; and 
• 
standardized reporting and recording is used, including for adverse events. 
Review of treatment and management protocols by an independent group of experts in clinical 
management and public health (e.g. the national MDR-TB advisory group) is
recommended.
DST is an important implementation consideration that will need further enhancement in many 
countries, given the increasing potential use of bedaquiline and linezolid (even for longer regimens for 
MDR/RR-TB), and the inclusion of new medicines (e.g. pretomanid) in MDR-TB treatment regimens. 
Baseline DST will confirm eligibility for the BPaL regimen; hence, the establishment and strengthening 
of DST services will be a vital consideration for implementation. 
In patients with bacteriologically confirmed MDR/RR-TB,
55
the MTBDRsl assay may be used as the initial 
test, in preference to culture and phenotypic DST, to detect resistance to fluoroquinolones (conditional 
recommendation; certainty of evidence for direct testing of sputum from low to moderate (33)). In 
settings in which laboratory capacity for DST to fluoroquinolones is not yet available, or cannot be 
accessed, it will be difficult to carry out operational research on BPaL. If testing for susceptibility to 
bedaquiline or linezolid is available, it is highly desirable to also carry this out at baseline and in the 
absence of culture conversion during treatment; however, such testing need not be a prerequisite for 
treatment initiation. Drug susceptibility testing for pretomanid is not yet available. 
Currently, there is limited capacity globally for DST for bedaquiline and linezolid; as these medicines 
and regimens become more widely used, laboratory capacity in this area should be strengthened. 
National and reference laboratories will need to have the reagents for DST available, and will need 
data on the MIC distribution of all M. tuberculosis lineages that are circulating globally. If resistance to 
any of the component medicines in the BPaL regimen is detected, treatment with a longer MDR-TB 
regimen should be started. The WHO SRL Network is available to support national TB reference 
laboratories in performing quality-assured DST. A WHO technical consultation in 2017 established 
54 
The protocol for the Nix-TB study is available at: https://clinicaltrials.gov/ct2/show/NCT02333799.
55 
MDR/RR-TB is usually confirmed by rapid molecular tests that detect resistance to rifampicin and M. tuberculosis. Current WHO 
recommendations state that Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic 
test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high-quality evidence). Xpert MTB/RIF should 
also be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children suspected of having MDR-TB 
or HIV-associated TB (strong recommendation, very low quality evidence) (24). A recent WHO rapid communication reinforced the 
high diagnostic accuracy and improved patient outcomes of rapid molecular diagnostic tests such as Xpert MTB/RIF, Xpert MTB/RIF 
Ultra and TrueNat (31). 

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Recommendations 
52
critical concentrations for DST for the fluoroquinolones, bedaquiline, delamanid, clofazimine and 
linezolid (58). Methods for testing pretomanid susceptibility are currently under
development.